Oxadiazole and thiadiazole derivatives of dihydropyridine NPY antagonists

ABSTRACT

A series of non-peptidergic antagonists of NPY have been synthesized and are comprised of oxadiazole, thiadiazole and thiadiazole oxide derivatives of dihydropyridines of Formula I.  
                 
 
     wherein B is  
                 
 
     with X being O, S or  
                 
 
     and X 1  is O or S.  
     As antagonists of NPY-induced behavior, these compounds are expected to act as effective anorexiant agents in promoting weight loss and treating eating disorders.

CROSS REFERENCE TO RELATED APPLICATION

[0001] This non-provisional application claims priority from provisionalapplication U.S. Ser. No. 60/216,985 filed Jul. 7, 2000.

FIELD OF THE INVENTION

[0002] The present invention is directed to heterocyclic compoundscomprising dihydropyridines having oxadiazole, thiadiazole,acylsemicarbazide and thioacylsemicarbazide moieties connected to the4-position of the pyridine ring. More particularly, the invention isdirected to NPY antagonist of oxadiazole and thiadiazole derivatives of1,4-dihydropyridine.

BACKGROUND OF THE INVENTION

[0003] Neuropeptide Y (NPY) is a 36 amino acid peptide first isolated in1982 from porcine brain. The peptide is a member of a larger peptidefamily which also includes peptide YY (PYY), pancreatic peptide (PP),and the non-mammalian fish pancreatic peptide Y (PY). Neuropeptide Y isvery highly conserved in a variety of animal, reptile and fish species.It is found in many central and peripheral sympathetic neutrons and isthe most abundant peptide observed in the mammalian brain. In the brain,NPY is found most abundantly in limbic regions. The peptide has beenfound to elicit a number of physiological responses including appetitestimulation, anxiolysis, hypertension, and the regulation of coronarytone.

[0004] Structure-activity studies with a variety of peptide analogs(fragments, alanine replacements, point mutations, and internaldeletion/cyclized derivatives) suggest a number of receptor subtypesexist for NPY. These currently include the Y₁, Y₂, Y₃, and theY_(1-like) or Y₄ subtypes.

[0005] Although a number of specific peptidic antagonists have beenidentified for most of the subtypes, few selective non-peptidicantagonists have been reported to date. The heterocyclic guanidinederivative He 90481 (4) was found to be a weak but competitiveantagonist of NPY-induced Ca⁺⁺ entry in HEL cells (pA₂=4.43). Thecompound was also found to have α₂-adrenergic and histaminergic activityat this dose range. D-Myo-inositol-1,2,6-triphosphate was reported to bea potent but non-competitive antagonist to NPY-induced contractions inguinea pig basilar artery. Similarly, the benextramine-likebisguanidines were reported to displace ³H-NPY in rat brain (IC₅₀, 19and 18.4 μM) and to display functional antagonism in rat femoral artery.The bisguanidine was shown to be functionally selective for the Y₂receptor since it antagonized the effect of the NPY₂ agonist NPY₁₃₋₃₆but had no effect on the vasoconstrictive activity of the NPY₁ agonist[Leu³¹, Pro³⁴]NPY as disclosed in J. Med. Chem., 1994, 37, 2242-48, C.Chauraisia, et al.

[0006] Compound BIBP 3226, as reported in K. Rudolf, et al., Eur. J.Pharmacol., 1994, 271, R111-R113, displaces I-125 Bolton-Hunter labeledNPY in human neuroblastoma cells (SK-N-MC). BIBP antagonized theNPY-induced increase in intracellular Ca⁺⁺ in SK-N-MC cells as well asantagonizing the NPY-induced pressor response in pithed rat experiments.

[0007] In addition to displacing I-125 labeled NPY and PYY in humanneuroblastoma cells, compound SR 120819A, as reported in C.Serradeil-LeGal, et al., FEBS Lett., 1995, 362, 192-A6, also antagonizedNPY-related increases in diastolic blood pressure in an anesthetizedguinea pig model.

[0008] Over the past two decades, extensive work has been conductedrelating to the 4-aryl-1,4-dihydropyridine class of compounds. Synthesesof compounds in this category have been driven by their pharmacologicalactions involving calcium channels rendering them useful for treatingcardiovascular disorders such as ischemia and hypertension.

[0009] Numerous prior patents and publications disclose variousdihydropyridine derivatives. One example is U.S. Pat. No. 4,829,076 toSzilagyi, et al. disclosing compounds of formula (1) as calciumantagonists for treating hypertension.

[0010] U.S. Pat. No. 5,635,503 to Poindexter, et al. discloses4-(3-substituted-phenyl)-1,4-dihydropyridine derivatives having NPYantagonist properties. These derivatives conform to structural formula(2).

[0011] In (2), B is either a covalent bond or the group —NH—. The symbolZ denotes hetaryl moieties, examples being homopiperazinyl orpiperazine.

[0012] U.S. Pat. No. 5,554,621 discloses related derivatives where Z isa fused ring or a spiro-fused nitrogen heterocycle. U.S. Pat. No.5,668,151 also discloses related derivatives where Z is a piperidinyl ortetrahydropyrindinyl.

[0013] The above-noted compounds have shown to posses antagonistactivity. However, there is a continuing need for dihydropyridinederivatives having improved NPY antagonist activity.

SUMMARY OF THE INVENTION

[0014] The present invention is directed to novel dihydropyridinederivatives having NPY antagonist activity. More particularly, theinvention is directed to oxadiazole and thiadiazole derivatives ofdihydropyridines.

[0015] Accordingly, one aspect of the invention is to providedihydropyridine derivatives that are effective in promoting weight lossand treating certain disorders in a mammal by administering to themammal an anorexiant effective dose of an active compound of theinvention.

[0016] A further aspect of the invention is to provide a method oftreating clinical disorders amenable to alleviation by eliciting an NPYY₁ response by administering to a patient an effective amount of acompound of the invention.

[0017] Another aspect of the invention is to provide a pharmaceuticalcomposition for use in promoting weight loss and treating eatingdisorders, where the composition comprises an anorexiant effectiveamount of an active compound of the invention and a pharmaceuticallyacceptable carrier.

[0018] The compounds of the invention have the Formula I and itspharmaceutically acceptable acid addition salts or hydrates thereof

[0019] wherein B is

[0020] with X being O, S or

[0021] and X¹ is O or S;

[0022] R¹ and R⁴ are independently selected from CO₂R⁶, cyano, and

[0023] where R⁶ is a lower alkyl;

[0024] R² and R³ are independently selected from hydrogen, cyano andlower alkyl;

[0025] R⁵ is selected from hydrogen and halogen;

[0026] n is an integer selected from 1 to 5;

[0027] in which R⁷ and R⁸ are independently selected from lower alkyland lower alkanol; R⁹ is selected from hydrogen, lower alkyl, —CO₂R⁶,—(CH₂)_(m)R¹⁰, hydroxy, cyano, and —(CH₂)_(m)NR¹¹R¹², wherein m is zeroor an integer from 1 to 3;

[0028] R¹⁰ is C₃₋₇ cycloalkyl, naphthyl, and

[0029] with R¹³ selected from the group consisting of lower alkyl, loweralkenyl, C₃₋₇ cycloalkyl, lower alkoxy, hydrogen, halogen, hydroxy,dialkylamino, phenoxy, amino, —NHCOR⁶, —CO₂R⁶, NO₂, trifluoromethyl, andphenyl, and R¹¹ and R¹² are independently selected from the groupconsisting of hydrogen, alkyl, cycloalkyl, alkylene, phenyl, alkylamino,heterocyclic alkyl, methoxy, cyano, lower alkanol, naphthyl, furfuryl,tetrahydrofurfuryl, thiophene, azetidine, lower alkyl esters,acetamides, and carbamates and where —NR¹¹R¹² is a heterocyclic amine orimine.

[0030] These and other aspects of the invention will become apparent toone skilled in the art as described in the following detaileddescription.

DETAILED DESCRIPTION OF THE INVENTION

[0031] The present invention is directed to novel compounds having NPYY₁ antagonist activity and pharmaceutical compositions containing thenovel compounds. The invention is further directed to a method oftreating clinical disorders, such as eating disorders, using the novelcompounds of the invention.

[0032] The compounds of the invention have the Formula I

[0033] The compounds within the perview of the invention include thepharmaceutically acceptable acid addition salts and/or hydrates of thecompounds of Formula I.

[0034] In the Formula I, B is

[0035] where X is O, S or

[0036] and X¹ is O or S;

[0037] wherein

[0038] R¹ and R⁴ are independently selected from CO₂R⁶, cyano, and

[0039] where R⁶ is a lower alkyl;

[0040] R² and R³ are independently selected from hydrogen, cyano andlower alkyl;

[0041] R⁵ is selected from hydrogen and halogen;

[0042] n is an integer selected from 1 to 5;

[0043] in which R⁷ and R⁸ are independently selected from lower alkyland lower alkanol; R⁹ is selected from hydrogen, lower alkyl, —CO₂R⁶,—(CH₂)_(m)R¹⁰, hydroxy, cyano, and —(CH₂)_(m)NR¹¹R¹², wherein

[0044] m is zero or an integer from 1 to 3;

[0045] R¹⁰ is C₃₋₇ cycloalkyl, naphthyl, and

[0046] with R¹³ being lower alkyl, lower alkenyl, C₃₋₇ cycloalkyl, loweralkoxy, hydrogen, halogen, hydroxy, dialkylamino, phenoxy, amino,—NHCOR¹, —CO₂R¹, NO₂, trifluoromethyl, phenyl, and R¹¹ and R¹² areindependently selected from the group consisting of hydrogen, alkyl,cycloalkyl, alkylene, phenyl, alkylamino, heterocyclic alkyl, methoxy,cyano, lower alkanol, naphthyl, furfuryl, tetrahydrofurfuryl, thiophene,azetidine, lower alkyl esters, acetamides, and carbamates and where—NR¹¹R¹² is a heterocyclic amine or imine.

[0047] The term “lower” refers to substituents such as alkyl or alkoxygroups that contain from one to four carbon atoms. Alkenyl groupsgenerally contain two to four carbon atoms. In embodiments of theinvention, R¹ is preferably CO₂R⁶ where R⁶ is methyl. R² and R³ arepreferably methyl. R⁵ is preferably hydrogen or fluorine. Z ispreferably 4-(3-methoxyphenyl)-1-piperidinyl,4-(cyclohexyl)-1-piperazinyl or 4-phenyl-1-piperazinyl.

[0048] The compounds of the present invention can exist as opticalisomers and both the racemic mixtures of these isomers as well as theindividual optical isomers themselves are within the scope of thepresent invention. The racemic mixtures can be separated into theirindividual isomers through well-known techniques such as the separationof the diastereomeric salts formed with optically active acids, followedby conversion back to the optically active bases.

[0049] As indicated, the present invention also pertains to thepharmaceutically acceptable non-toxic salts of these basic compounds.Such salts include those derived from organic and inorganic acids suchas, without limitation, hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid, methanesulfonic acid, acetic acid, dichloroaceticacid, tartaric acid, lactic acid, succinic acid, citric acid, maleicacid, fumaric acid, sorbic acid, aconitic acid, salicyclic acid,phthalic acid, enanthic acid, and the like.

[0050] The dihydropyridine oxadiazole compounds of Formula I can beprepared by several processes. Generally, an amine (II), such as apiperidine or piperazine is alkylated with either methyl bromoacetate,methyl acrylate or ethyl 3-bromobutanoate to yield the correspondingester (III). The ester (III) is then converted to the hydrazidederivative (IV) by treating with hydrazine in refluxing ethanol. Thehydrazide (IV) is reacted with the starting dihydropyridine isocyanate(V) to form the acyl- or thioacylsemicarbazides (VI). The processproceeds according to the following Scheme.

[0051] The isocyanate (V) can be produced by various processes as knownin the art. For example, the starting aniline dihydropyridine (VII) canbe converted to the carbamate (VIII) with ClCO₂Me with pyridine indichloromethane. The carbamate (VIII) is then converted to theisocyanate (V) by reacting with B-catecholborane with Et₃N in THF usingthe method of V. L. K. Valli and H. Alper, J. Org. Chem., 1995, 60,257-258. The isocyanate can be produced according to the followingScheme.

[0052] A preferred method for producing the oxadiazoles or thiadiazolesof Formula (I) forms a solution of the acyl- or thioacylsemicarbazide(VI) in 1,2-dichloroethane. PPh₃ and CCl₄ are then added to the solutionand stirred. The solvent is removed and purified by flashchromatography.

[0053] The oxadiazoles and thiadiazoles also can be prepared by analternative method by treating the acyl- or thioacylsemicarbazide withPOCl₃ in toluene by heating with a steam bath. The oxadiazole andthiadiazole of Formula la are produced from the isocyanate derivativeaccording to the following Scheme.

[0054] In an alternative process of producing the thiadiazole of FormulaIb, the corresponding acylsemicarbazide (VIa) is treated with Lawesson'sreagent in toluene and warmed to reflux. The process proceeds accordingto the following Scheme.

[0055] The synthesis of the thiadiazole oxide was accomplished accordingto the Scheme below. The aniline dihydropyridine (V) is converted to thethiadiazole oxide (IX) intermediate by way of AlMe₃ and Weinstock'salkylating agent (S. Karady, J. S. Amato, D. Dortmond, L. M. Weinstock,Heterocycles, 1981, 16, 1561-1568). The thiadiazole oxide intermediate(IX) is converted to the thiadiazole oxide of Formula I by alkylationwith an amine. By way of example, the thiadiazole oxide intermediate(IX) is converted to the thiadiazole oxide of Formula (XI) by alkylationwith 4-(3-methoxyphenyl)-1-piperdinepropanamine (XII).

[0056] The alkyl amines, such as the propanamines are produced by knownprocesses. The amines can be produced from the appropriate secondaryamines by conjugate addition to acrylonitrile in methanol. The reactionproduct is then hydrogenated catalytically in the presence of a Raneynickel catalyst in methanol to yield the amine as follows.

[0057] a: acrylonitrile, MeOH, Δ. b: H₂, NH₃, Raney Nickel, MeOH.

[0058] The alkyl piperazine can be synthesized using standard proceduresby N-alkylation of the respective piperazine followed by removal of theBoc protecting groups as follows.

[0059] a: (Bromomethyl)cyclopropane, K₂CO₃, MeCN, Δ. b: 3N HCl, MeOH.

[0060] The Boc protecting group can also be cleaved from theintermediate in methanol and HCl to produce the unsubstituted piperazinederivative as follows.

[0061] The compounds of the invention demonstrate binding affinity atNPY Y₁ receptors. This pharmacologic activity is assayed in SK-N-MC(human neuroblastoma) cell membranes using iodine-125-labeled I-PYY as aradioligand. The compounds of Formula I had good binding affinities asevidenced by IC₅₀ values being about 10 μM or less at NPY Y₁ receptors.Preferred compounds have IC₅₀ values less than 100 nM and most preferredcompounds have IC₅₀ values of less than 10 nM.

[0062] Pharmacologically, the compounds of Formula I act as selectiveNPY antagonists at NPY Y₁ receptor sites. As such, the compounds ofFormula I are of value in the treatment of a wide variety of clinicalconditions which are characterized by the presence of an excess ofneuropeptide Y. Thus, the invention provides methods for the treatmentor prevention of a physiological disorder associated with an excess ofneuropeptide Y, which method comprises administering to a mammal in needof treatment an effective amount of a compound of Formula I or apharmaceutically acceptable salt, solvate or prodrug thereof. The term“physiological disorder associated with an excess of neuropeptide Y”encompasses those disorders associated with an inappropriate stimulationof neuropeptide Y receptors, regardless of the actual amount ofneuropeptide Y present in the locale.

[0063] These physiological disorders include:

[0064] disorders or diseases pertaining to the heart, blood vessels orthe renal system, such as vasospasm, heart failure, shock, cardiachypertrophy, increased blood pressure, angina, myocardial infarction,sudden cardiac death, congestive heart failure, arrhythmia, peripheralvascular disease, and abnormal renal conditions such as impaired flow offluid, abnormal mass transport, or renal failure;

[0065] conditions related to increased sympathetic nerve activity forexample, during or after coronary artery surgery, and operations andsurgery in the gastrointestinal track;

[0066] cerebral diseases and diseases related to the central nervoussystem, such as cerebral infarction, neurodegeneration, epilepsy,stroke, and conditions related to stroke, cerebral vasospasm andhemorrhage, depression, anxiety, schizophrenia, dementia, seizure, andepilepsy;

[0067] conditions related to pain or nociception;

[0068] diseases related to abnormal gastrointestinal motility andsecretion, such as different forms of ileus, urinary incontinence, andCrohn's disease;

[0069] abnormal drink and food intake disorders, such as obesity,anorexia, bulemia, and metabolic disorders;

[0070] diseases related to sexual dysfunction and reproductive disorderssuch as benign prostatic hyperplasia and male erectile dysfunction;

[0071] conditions or disorders associated with inflammation;

[0072] respiratory diseases, such as asthma and conditions related toasthma and bronchoconstriction;

[0073] diseases related to abnormal hormone release, such as leutinizinghormone, growth hormone, insulin and prolactin; and

[0074] sleep disturbance and diabetes.

[0075] There is evidence that NPY contributes to certain symptoms inthese disorders, such as, hypertension, eating disorders, anddepression/anxiety, as well as circadian rhythms. Compounds of thisinvention are expected to be useful in treating these disorders as wellas sleep disturbance and diabetes.

[0076] Selected compounds are tested further for their ability to blockor stimulate NPY-induced feeding in test animals by intraperitonealadministration to the animal prior to inducing feeding behavior withNPY. Taken together, these tests indicate that the compounds of thisinvention would be useful anorexiants and would function as anti-obesityagents with further use in various clinical eating disorders. Thus,another aspect of the invention concerns a process for reducing foodintake in an obese mammal or a mammal with an eating disorder. Theprocess comprises systemic administration to such a mammal of ananorexiant-effective dose of a Formula I compound or a pharmaceuticallyacceptable acid addition salt and/or hydrate thereof.

[0077] On the basis of pharmacologic testing, an effective dose givenparenterally could be expected to be in a range of about 0.05 to 1 mg/kgbody weight and if given orally would be expected to be in the range ofabout 1 to 50 mg/kg body weight.

[0078] For clinical applications, however, the dosage and dosage regimenmust in each case be carefully adjusted, utilizing sound professionaljudgment and considering the age, weight and condition of the recipient,the route of administration and the nature and gravity of the illness.Generally, the compounds of the instant invention will be administeredin the same manner as for available anorexiant drugs such asDiethylpropion, Mazindol, or Phentermine and the daily oral dose wouldcomprise from about 70 to about 1400 mg, preferably 500 to 1000 mgadministered from 1 to 3 times a day. In some instances, a sufficienttherapeutic effect can be obtained at lower doses while in others,larger doses will be required.

[0079] The term systemic administration as used herein refers to oral,buccal, transdermal, rectal, and parenteral (i.e. intramuscular,intravenous, and subcutaneous) routes. Generally, it will be found thatwhen a compound of the present invention is administered orally, whichis the preferred route, a larger quantity of reactive agent is requiredto produce the same effect as a smaller quantity given parenterally. Inaccordance with good clinical practice, it is preferred to administerthe instant compounds at a concentration level that will produceeffective anoretic effects without causing any harmful or untoward sideeffects. Similarly, the instant compounds can be administered to treatthe various diseases, conditions, and disorders listed above.

[0080] Therapeutically, the compounds of Formula I are generally givenas pharmaceutical compositions comprised of an effective anorecticamount of a compound of Formula I or a pharmaceutically acceptable acidaddition salt thereof and a pharmaceutically acceptable carrier.Pharmaceutical compositions for effecting such treatment will contain amajor or minor amount, e.g. from 95 to 0.5% of at least one compound ofthe present invention in combination with the pharmaceutical carrier.The carrier comprises one or more solid, semi-solid, or liquid diluent,filler, and formulation adjuvant that is non-toxic, inert andpharmaceutically acceptable.

[0081] Such pharmaceutical compositions are preferably in dosage unitforms; i.e., physically discrete units containing a predetermined amountof the drug corresponding to a fraction or multiple of the dose which iscalculated to produce the desired therapeutic response. The dosage unitscan contain 1, 2, 3, 4, or more single doses, or, alternatively,one-half, one-third, or one-fourth of a single dose. A single dosepreferably contains an amount sufficient to produce the desiredtherapeutic effect upon administration at one application of one or moredosage units according to the pre-determined dosage regimen usually awhole, half, third, or quarter of the daily dosage administered once,twice, three, or four times a day. Other therapeutic agents can also bepresent. Pharmaceutical compositions which provide from about 50 to 1000mg of the active ingredient per unit dose are preferred and areconventionally prepared as tablets, lozenges, capsules, powders,transdermal patches, aqueous or oily suspensions, syrups, elixirs, andaqueous solutions. Preferred oral compositions are in the form oftablets or capsules and may contain conventional excipients such asbinding agents (e.g. syrup, acacia, gelatin, sorbitol, tragecanth, orpolyvinylpyrrolidone), fillers (e.g. lactose, sugar, maize-starch,calcium phosphate, sorbitol, or glycine), lubricants (e.g. magnesiumstearate, talc, polyethylene glycol or silica), disintegrants (e.g.starch) and wetting agents (e.g. sodium lauryl sulfate).

[0082] Solutions or suspensions of a Formula I compound withconventional pharmaceutical vehicles are generally employed forparenteral compositions such as an aqueous solution for intravenousinjection or an oily suspension for intramuscular injection. Suchcompositions having the desired clarity, stability and adaptability forparenteral use are obtained by dissolving from 0.1% to 10% by weight ofthe active compound in water or a vehicle consisting of a polyhydricaliphatic alcohol such as glycerin, propylene glycol, and polyethyleneglycols or mixtures thereof. The polyethylene glycols consist of amixture of non-volatile, usually liquid, polyethylene glycols which aresoluble in both water and organic liquids and which have molecularweights from about 200 to 1500.

DESCRIPTION OF THE SPECIFIC EMBODIMENTS

[0083] The compounds of Formula I were prepared in the followingExamples. All catalytic hydrogenations were performed with ParrHydrogenators (Parr Instrument Co.) Bulb-to-bulb distillations werecarried out on a Kugelrohr apparatus (Aldrich). Solvate removal fromsolids, when noted, was carried out under vacuum drying overnight in anAbderhalden drying pistol over refluxing ethanol. All melting pointswere obtained using a Thomas-Hoover melting point apparatus and arecorrected. ¹H and ¹³C NMR were obtained using a Brucker AM-300 NMRspectrometer at 300 and 75.5 MHz, respectively. NMR solvents used weredueterochloroform (CDCl₃), methyl-d₆-sulfoxide (DMSO-d₆) and deuteriumoxide (D₂O).

General Procedure for the Preparation of Esters of Examples 1-7

[0084] A mixture of the appropriate piperidine or piperazine (30 mmol),bromo ester (35 mmol), K₂CO₃ (40 mmol) and 80 mL of MeCN was refluxedovernight under N₂. After cooling to room temperature, the volatileswere removed in vacuo and the residue taken up in H₂O and extracted withCH₂Cl₂. The combined organic extracts were then washed with H₂O, brine,dried over MgSO₄, filtered and concentrated. The crude products weresubjected to flash chromatography (SiO₂:MeOH:EtOAc, or CH₂Cl₂) to affordthe purified products.

EXAMPLE 1 Preparation of 4-(3-Methoxyphenyl)-1-piperidineacetic Acid,Methyl Ester, Maleic Acid Salt

[0085] The compound prepared by the above method was isolated afterchromatography (74% yield) as a clear oil. The compound was isolated asa low melting waxy solid and characterized as the maleic acid salt: ¹HNMR (DMSO-d₆) δ 7.24 (m, 1 H), 6.80 (m, 3 H), 6.08 (s, 2 H), 4.13 (s 2H), 3.76 (s, 3 H), 3.74 (s, 3 H), 3.42 (m, 2 H), 3.04, (m, 2 H), 2.72(p, 2 H, J=7.9 Hz), and 1.92 (m, 4 H); ¹³C NMR (DMSO-d₆) δ 167.2, 159.4,146.0, 135.0, 129.6, 118.7, 112.5, 111.8, 55.5, 54.9, 52.0, 39.0, and29.7. Analysis calculated for C₁₅H₂₁NO₃.C₄H₄O₄.0.25 H₂O: C, 59.45; H,6.70; N, 3.65. Found: C, 59.45; H, 6.80; N, 3.47.

EXAMPLE 2 Preparation of 3-[4-(3-Methoxyphenyl)-1-piperidinebutanoicAcid, Methyl Ester, Maleic Acid Salt

[0086] The compound was isolated as a clear oil (86% yield) afterchromatography and converted to the maleic acid salt. The salt wasisolated as a colorless solid after recrystallization from Et₂O/MeCN: mp103-4° C.; ¹H NMR (DMSO-d₆) δ 7.24 (t, 1 H, J=7.8 Hz), 6.79 (m, 3 H),6.03 (s, 2 H), 4.06 (q, 2 H, J=7.1 Hz), 3.72 (s, 3 H), 3.51 (m, 2 H),3.36 (m, 2 H), 3.06 (m, 4 H), 2.79 (m, 1 H), 2.41 (t, 2 H, J=7.2 Hz),1.88 (m, 6 H), and 1.79 (t, 3 H, J=7.1 Hz); ¹³C NMR (DMSO-d₆) δ 172.0,167.3, 159.5, 145.8, 136.1, 129.7, 118.7, 112.6, 111.9, 60.2, 55.4,55.0, 52.1, 38.7, 30.4, 19.2, and 14.1. Analysis calculated forC₁₈H₂₇NO₃.C₄H₄O₄: C, 62.69; H, 7.41; N, 3.32. Found: C, 62.59; H, 7.26;N, 3.09.

EXAMPLE 3 Preparation of 2-[4-(3-Methoxyphenyl)-1-piperidinepropionicAcid, Methyl Ester

[0087] A solution of the piperidine (5.85 g, 30.6 mmol) and methylacrylate (8.9 mL) was stirred at room temperature for 2.5 h. Thevolatiles were removed in vacuo and the residue then filtered through aplug of SiO₂ to furnish the acylsemicarbazide (7.83 g, 93% yield) as avery pale yellow oil: ¹H NMR (CDCl₃) δ 7.19 (t, 1 H, J=7.8 Hz), 6.73 (m,3 H), 3.76 (s, 3 H), 3.67 (s, 3 H), 3.01 (m, 2 H), 2.75 (m, 2 H), 2.53(m, 2 H), 2.42 (m, 1 H), 2.09 (m, 2 H), and 1.76 (m, 4 H), ¹³C NMR(CDCl₃) δ 173.1, 159.7, 148.1, 129.4, 119.3, 112.7, 111.4, 55.2, 54.1,54.0, 51.7, 42.7, 33.5, and 32.3. Anal. Calcd for C₁₆H₂₃NO₃: C, 69.29;H, 8.36; N, 5.05. Found: C, 69.08; H, 8.14; N, 5.04.

EXAMPLE 4 Preparation of 4-Phenyl-1-piperidineacetic Acid, Methyl Ester

[0088] The compound was prepared in a manner similar to that describedin Example 1. After chromatography, the compound was isolated as ayellow oil (34% yield): ¹H NMR (CDCl₃) δ 7.35 (m, 5 H), 3.75 (s, 3 H),3.30 (s, 2 H), 3.08 (m, 2 H), 2.51 (m, 1 H), 2.30 (m, 2 H), 1.88 (m, 4H).

EXAMPLE 5 Preparation of 4-Phenyl-1-piperazineacetic Acid, Methyl Ester

[0089] The compound was prepared in a manner similar to that describedin Example 1. The compound was isolated as a pale yellow oil (39% yield)after flash chromatography: ¹H NMR (CDCl₃) δ 7.24 (m, 2 H), 6.88 (m, 3H), 3.73 (s, 3 H), 3.26 (m, 6 H), 2.76 (t, 4 H, J=5.0 Hz), ¹³C NMR(CDCl₃) δ 170.7, 151.3, 129.2, 119.5, 116.3, 59.4, 53.1, 51.8, 49.1.Analysis calculated for C₁₃H₁₈N₂O₂: C, 66.64; H, 7.74; N, 11.96. Found:C, 66.36; H, 7.69; N, 11.82.

EXAMPLE 6 Preparation of 4-(1-Piperidinyl)-1-piperidineacetic Acid,Methyl Ester

[0090] The reaction afforded an amber oil (53% yield) and was taken ontothe next reaction without further characterization: ¹H NMR (CDCl₃) δ3.70 (m, 3 H), 3.19 (s, 2 H), 2.98 (d, 2 H, J=11.4 Hz), 2.54 (m, 4 H),2.35 (m, 1 H), 2.15 (m, 2 H), 1.68 (m, 8 H), 1.43 (m, 2 H).

EXAMPLE 7 Preparation of 4-Cyclohexyl-1-piperazineacetic Acid, MethylEster

[0091] The compound was prepared according to standard literatureprocedure and obtained as a yellow oil (31% yield) after columnchromatography and was used without further characterization.

General Procedure for the Preparation of Hydrazides of Examples 8-14

[0092] A solution of the acylsemicarbazide (23 mmol), NH₂NH₂.H₂O (69mmol) and 65 mL of EtOH was refluxed overnight (20 h). The solvents werethen removed in vacuo and the residues purified by flash chromatography(SiO₂:MeOH/CHCl₃ or CH₂Cl₂) to furnish the purified products as oils orlow melting solids.

EXAMPLE 8 4-(3-Methoxyphenyl)-1-piperidineacetic Acid Hydrazide

[0093] The compound was isolated as a clear oil (92% yield) which slowlysolidified on standing at room temperature to a colorless solid: mp82-3° C.; ¹H NMR (CDCl₃) δ 8.22 (br s, 1 H), 7.22 (m, 1 H), 6.74 (m, 3H), 3.86 (br s, 2 H), 3.79 (s, 3 H), 3.09 (s, 2 H), 2.91 (m, 2 H), 2.46(m, 1 H), 2.25 (m, 2 H), and 1.45 (m, 4 H); ¹³C NMR (CDCl₃) δ 170.9,159.8, 147.6, 129.5, 119.2, 112.8, 111.4, 61.1, 55.2, 55.0, 42.0, and33.6. Analysis calculated for C₁₄H₂₁N₃O₂: C, 63.85; H, 8.04; N, 15.96.Found: C, 63.70; H, 7.96; N, 15.69.

EXAMPLE 9 2-[4-(3-Methoxyphenyl)-1-piperidinepropionic Acid Hydrazide

[0094] The compound was isolated as a clear oil (57% yield): ¹H NMR(DMSO-d₆) δ 9.00 (br s, 1 H)m 7.19 (t, 1 H, J=7.8 Hz), 6.75 (m 3 H),4.14 (m, 2 H), 3.72 (s, 3 H), 2.92 (m, 2 H), 2.50 (t, 2 H, J=7.1 Hz),2.45 (m, 1 H), 2.20 (t, 2 H, J=7.1 Hz), 1.97 (m, 2 H), and 1.66 (m, 4H).

EXAMPLE 10 3-[4-(3-Methoxyphenyl)-1-piperidinebutanoic Acid Hydrazide,Hydrochloride Salt

[0095] After chromatography, the compound was isolated as a clear oil(60% yield) and then a small portion converted to the HCl salt: mpindistinct; ¹H NMR (DMSO-d₆) δ 11.26 (brs, 1 H), 11.05 (brs, 1 H), 10.56(br s, 2 H), 7.25 (t, 1 H, J=8.3 Hz), 6.81 (m, 3 H), 3.73 (s, 3 H), 3.52(m, 2 H), 3.04 (m, 4 H), 2.79 (m, 1 H), 2.38 (m, 2 H), and 2.00 (m, 6H); ¹³C NMR (DMSO-d₆) δ 170.6, 159.4, 146.0, 129.7, 118.7, 112.7, 111.7,55.1, 55.0, 51.9, 38.7, 29.9, 29.6, and 19.0. Analysis calculated forC₁₆H₂₅N₃O₂.2HCl.0.75 H₂O: C, 50.86; H, 7.60; N, 11.12. Found: C, 51.02;H, 7.77, N, 11.08.

EXAMPLE 11 4-Phenyl-1-piperidineacetic Acid, Hydrazide

[0096] This compound was isolated as an orange solid (71% yield): mp88-90° C.; ¹H NMR (CDCl₃) δ 8.21 (br s, 1 H), 7.27 (m, 6 H), 3.86 (br s,1 H), 3.10 (s, 2 H), 2.93 (d, 2 H, J=11.5 Hz), 2.50 (m, 1 H), 2.28 (m, 2H), 1.77 (m, 4 H); ¹³C NMR (CDCl₃) δ 170.9, 145.8, 128.6, 126.8, 126.4,61.2, 55.0, 41.9, 33.7, Analysis calculated for C₁₃H₁₉N₃O: C, 66.92; H,8.21; N, 18.01. Found: C, 66.65; H, 8.48; N, 18.18.

EXAMPLE 12 4-Phenyl-1-piperazineacetic Acid, Hydrazide

[0097] After chromatography, the compound was obtained as a white solid(90% yield): mp 90-93° C.; ¹H NMR (DMSO-d₆) δ 8.98 (br s, 1 H), 7.20 (t,2 H, J=7.8 Hz), 6.91 (d, 2 H, J=8.4 Hz), 6.77 (t, 1 H, J=7.2 Hz), 4.28(br s, 2 H), 3.13 (m, 4 H), 2.98 (s, 2 H), 2.59 (m, 4 H); ¹³C NMR(DMSO-d₆) δ 168.2, 151.0, 128.9, 118.8, 115.4, 59.9, 52.8, 48.1.Analysis calculated for C₁₂H₁₈N₄O: C, 61.52; H, 7.74; N, 23.91. Found:C, 61.49; H, 7.59; N, 23.96.

EXAMPLE 13 4-Cyclohexyl-1-piperazineacetic Acid, Hydrazide

[0098] This addition product of the hydrazide was furnished as a paleyellow solid (78% yield): mp indistinct; ¹H NMR (DMSO-δ₆) δ 8.78 (s, 1H), 4.15 (br s, 2 H), 3.35 (br s, 2 H), 2.85 (s, 2 H), 2.43 (m, 6 H),2.15 (m, 1 H), 1.70 (m, 4 H), 1.55 (m, 1 H), 1.13 (m, 5 H).

EXAMPLE 14 4-(1-Piperidinyl)-1-piperidineacetic Acid, Hydrazide

[0099] The compound was obtained as a pale yellow residue (23% yield):¹H NMR (DMSO-δ₆) δ 8.84 (s, 1 H), 3.50 (br s, 2H), 2.94 (m, 2 H), 2.86(s, 4 H), 2.16 (m, 1 H), 1.95 (m, 2 H), 1.63 (m, 2 H), 1.45 (m, 10 H),¹³C NMR (DMSO-δ₆) δ 168.4, 61.6, 60.0, 53.1, 49.7, 27.3, 25.9, 24.4.HRMS Calcd. for C₁₂H₂₅N₄O(M+H): 241.2028. Found: 241.2031.

General Procedure for the Preparation of Acyl- andThioacylsemi-carbazides of Examples 15-24

[0100] To a solution of the starting hydrazide (22.8 mmol) in 65 mL ofCH₂Cl₂, was added the corresponding isocyanate or thioisocyanate (23.0mmol). The resulting solution was stirred overnight (15 h) at roomtemperature and then washed with H₂O, brine, and dried over Na₂SO₄.After filtration and concentration in vacuo, the residue was used crudeor purified by flash chromatography (SiO₂:MeOH/CH₂Cl₂). The followingAcyl- and Thioacylsemicarbazides were obtained.

EXAMPLE 154-[3-[[[2-[4-(3-Methoxyphenyl)-1-piperidinyl]acetyl]hydrazino]carbonyl]amino]phenyl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylicAcid, Dimethyl Ester

[0101] The compound was obtained as a clear foam (26% yield): mpindistinct; ¹H NMR (DMSO-d₆) δ 9.51 (br s, 1 H), 8.88 (br s, 1 H), 8.66(br s, 1 H), 7.88 (br s, 1 H), 7.21 (m, 3 H), 7.07 (t, 1 H, J=7.7 Hz),6.76 (m, 4 H), 4.86 (s, 1 H), 3.73 (s, 3 H), 3.55 (s, 6 H), 3.34 (s, 2H), 3.02 (m, 2 H), 2.45 (m, 1 H), 2.25 (s, 6 H), 2.19 (m, 2 H), and 1.71(m, 4 H); ¹³C NMR (DMSO-d₆) δ 169.4, 167.4, 159.3, 155.2, 148.2, 148.0,145.6, 139.9, 129.3, 128.3, 120.6, 118.9, 117.1, 116.1, 112.5, 111.3,101.3, 60.3, 54.9, 53.8, 50.6, 38.4, 32.9, and 18.2. Analysis calculatedfor C₃₂H₃₉N₅O₇ 0.81 H₂O: C, 61.96; H, 6.60; N, 11.29. Found: C, 61.96;H, 6.38, N, 11.23.

EXAMPLE 164-[3-[[[2-[3-[4-(3-Methoxyphenyl)-1-piperidinyl]-1-oxopropyl]hydrazino]carbonyl]amino]phenyl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylicAcid, Dimethyl Ester

[0102] This compound was obtained as a creamy white foam (29% yield): mpindistinct; ¹H NMR (CDCl₃) δ 8.29 (br s, 1 H), 8.16 (br s, 1 H), 7.20(m, 4 H), 7.07 (t, 1 H, J=7.7 Hz), 6.97 (d, 1 H, J=7.9 Hz), 6.74 (m, 4H), 4.97 (s, 1 H), 3.78 (s, 3 H), 3.59 (s, 6 H), 3.01 (m, 2 H), 2.60 (m,2 H), 2.43 (m, 3 H), 2.20 (s, 6 H), 2.03 (m, 2 H), and 1.78 (m, 4 H);¹³C NMR (CDCl₃) δ 171.6, 168.4, 159.7, 155.3, 148.4, 147.6, 145.4,138.6, 129.5, 128.5, 122.8, 119.4, 118.8, 117.8, 112.9, 111.4, 103.1,55.2, 53.6, 51.0, 42.4, 39.0, 33.1, 31.0, and 19.1. Analysis calculatedfor C₃₃H₄₁N₅O₇.0.50 H₂O: C, 63.05; H, 6.73; N, 11.14. Found: C, 63.04;H, 6.66; N, 11.12.

EXAMPLE 174-[3-[[[2-[4-[4-(3-Methoxyphenyl)-1-piperidinyl]-1-oxobutyl]hydrazino]carbonyl]amino]phenyl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylicAcid, Dimethyl Ester

[0103] The compound was obtained as a pale pink solid (68% yield): mp108-112° C. (sintered); ¹H NMR (DMSO-d₆) δ 9.66 (br s, 1 H), 8.89 (br.s, 1 H), 8.66 (br s, 1 H), 8.26 (brs, 1 H), 7.19 (m, 3 H), 7.07 (t, 1 H,J=7.8 Hz), 6.77 (m, 4 H), 4.87 (s,. 1 H), 3.73 (s, 3 H), 3.56 (s, 6 H),2.97 (m, 2 H), 2.50 (m, 1 H), 2.34 (m, 2 H), 2.26 (s, 6 H), 2.18 (t, 2H, J=7.3 Hz), 1.98 (m, 2 H), and 1.67 (m, 6 H); ¹³C NMR (DMSO-d₆) δ172.1, 167.4, 159.3, 155.3, 148.2, 148.0, 145.7, 139.4, 129.3, 128.3,120.6, 118.9, 117.2, 116.2, 112.4, 111.4, 101.3, 57.5, 54.9, 53.7, 50.6,42.0, 33.0, 31.2, 22.3, and 18.2. Analysis calculated forC₃₄H₄₃N₅O₇.0.24 H₂O: C, 64.01; H, 6.87; N, 10.98. Found: C, 64.01; H,6.93; N, 10.79.

EXAMPLE 184-[3-[[[2-[(4-Phenyl-1-piperidinyl)acetyl]-hydrazino]-carbonyl]amino]phenyl]1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylicAcid, Dimethyl Ester

[0104] The compound was isolated as an off-white solid (99% yield): mp138-143° C. (sintered); ¹H NMR (DMSO-d₆) δ 8.88 (s, 1 H), 8.66 (s, 1 H),7.88 (s, 1 H), 7.24 (m, 7 H), 7.07 (t, 1 H, J=7.7 Hz), 6.73 (d, 1 H,J=7.7 Hz), 4.87 (s, 1 H), 3.56 (s, 6 H), 3.35 (s, 2 H), 3.00 (m, 4 H),2.46 (m, 2 H), 2.35 (m, 8 H), 1.77 (m, 4 H); ¹³C NMR (DMSO-d₆) δ 169.4,167.4, 155.2, 148.2, 146.3, 145.7, 139.3, 128.3, 126.7, 120.6, 117.1,116.1, 101.3, 60.2, 54.9, 50.6, 40.4, 38.4, 18.2. Analysis calculatedfor C₃₁H₃₇N₅O₆.1.0 H₂O: C, 62.72; H, 6.62; N, 11.80. Found: C, 62.68; H,6.52; N, 11.68.

EXAMPLE 194-[3-[[[2-[(4-Phenyl-1-piperidinyl)acetyl]-hydrazino]-carbonothioyl]amino]phenyl]1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylicAcid, Dimethyl Ester

[0105] This compound was obtained as a light yellow solid (95% yield):mp 125-130° C. (sintered); ¹H NMR (DMSO-d₆) δ 9.50 (br s, 1 H), 8.93 (s,1 H), 7.21 (m, 8 H), 6.92 (d, 1 H, J=7.3 Hz), 4.90 (s, 1 H), 2.26 (s, 6H), 2.19 (m, 2 H), 1.78 (m, 4 H); ¹³C NMR (DMSO-d₆) δ 180.3, 167.3,148.7, 146.3, 145.9, 138.9, 128.3, 127.6, 126.7, 123.6, 101.3, 60.3,54.9, 50.7, 41.3, 38.3, 32.9, 18.3. Analysis calculated forC₃₁H₃₇N₅O₅S.1.0 H₂O: C, 61.07; H, 6.45; N, 11.49. Found: C, 61.08; H,6.51; N, 11.35.

EXAMPLE 204-[3-[[[2-[[4-(3-Methoxyphenyl)-1-piperidinyl)acetyl]-hydrazino]-carbonothioyl]amino]phenyl]1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylicAcid, Dimethyl Ester

[0106] The compound was isolated as a light yellow solid (quantitative):mp 113-116 ° C. (sintered); ¹H NMR (DMSO-d₆) δ 9.51 (br s, 1 H), 8.92(s, 1 H), 7.23 (m, 5 H), 6.91 (d, 1 H, J=7.3 Hz), 6.78 (m, 4 H), 4.88(s, 1 H), 3.73 (s, 3 H), 3.55 (s, 6 H), 3.10 (s, 2 H), 2.98 (br s, 2 H),2.26 (s, 6 H), 2.19 (m, 3 H), 1.75 (m, 4 H); ¹³C NMR (DMSO-d₆) δ 167.3,159.3, 147.9, 145.9, 138.9, 129.3, 118.9, 112.5, 111.3, 101.2, 54.9,53.9, 50.7, 38.3, 32.8, 18.2. Analysis calculated for C₃₂H₃₉N₅O₆S.0.85H₂O: C, 60.33; H, 6.44; N, 10.99. Found: C, 60.68; H, 6.41; N, 10.56.

EXAMPLE 214-[3-[[[2-[(4-Phenyl)-1-piperazinyl]acetyl]-hydrazino]-carbonothioyl]amino]phenyl]1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylicAcid, Dimethyl Ester

[0107] This compound was isolated as a white solid (97%): mp 171-175° C.(sintered); ¹H NMR (DMSO-d₆) δ 9.51 (br s, 1 H), 8.94 (s, 1 H), 7.25 (m,5 H), 6.94 (d, 3 H, J=8.0 Hz), 6.77 (t, 1 H, J=7.2 Hz), 4.92 (s, 1 H),3.56 (s, 6 H), 3.15 (m, 8 H), 2.66 (br s, 4 H), 2.28 (s, 6 H); ¹³C NMR(DMSO-d₆) δ 180.5, 167.4, 151.0, 147.8, 145.9, 138.9, 128.9, 127.6, 118.8, 115.3, 101.3, 59.9, 52.8, 50.7, 48.0, 38.3, 18.3. Analysiscalculated for C₃₀H₃₆N₆O₆S.H₂O: C, 60.33; H, 6.16; N, 14.10. Found: C,60.35; H, 6.23; N, 13.95.

EXAMPLE 224-[4-Fluoro-3-[[[2-[[4-(3-methoxyphenyl)-1-piperidinyl]acetyl]-hydrazino]-carbonothioyl]amino]phenyl]1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylicAcid, Dimethyl Ester

[0108] This compound was isolated as a white solid (98%): mp 114-120° C.(sintered); ¹H NMR (DMSO-d₆) δ 8.96 (s, 1 H), 7.20 (t, 2 H, J=7.7 Hz),7.04 (m, 2 H), 6.78 (m, 3 H), 4.86 (s, 1 H), 3.73 (s, 3 H), 3.55 (s, 6H), 3.33 (br s, 2 H), 3.08 (s, 2 H), 2.96 (m, 2 H), 2.45 (m, 1 H), 2.26(s, 6 H), 2.18 (m, 2 H); ¹³C NMR (DMSO-d₆) δ 167.2, 159.3, 148.0, 145.9,143.4, 129.3, 126.4, 118.9, 114.8, 112.5, 111.3, 101.3, 60.2, 54.9,53.9, 50.7, 41.4, 37.9, 32.8, 32.8, 18.2. Analysis calculated forC₃₂H₃₈FN₅O₆S.1.0 H₂O: C, 58.43; H, 6.13; N, 10.65. Found: C, 58.70; H,6.10; N, 10.81.

EXAMPLE 234-[3-[[[2-[[4-(1-Piperidinyl)-1-piperidinyl]acetyl]-hydrazino]-carbonothioyl]amino]phenyl]1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylicAcid, Dimethyl Ester

[0109] This compound was obtained as a yellow solid (36%): mpindistinct; ¹H NMR (DMSO-d₆) δ 7.24 (m, 3 H), 6.87 (d, 1 H, J=7.8 Hz),4.88 (s, 1 H), 3.55 (s, 6 H), 3.44 (m, 4 H), 2.95 (m, 1 H), 2.73 (m, 1H), 2.26 (s, 8 H), 2.08 (m, 1 H), 1.73 (m, 1 H), 1.38 (M, 4 H); ¹³C NMR(DMSO-d₆) δ 167.2, 149.8, 147.9, 146.3, 145.8, 139.3, 129.7, 127.8,126.8, 123.9, 121.6, 101.1, 52.7, 50.7, 49.5, 38.3, 26.8, 18.3. HRMScalculated for C₃₀H₄₃N₆O₅S (M+H): 599.3016. Found: 599.3034.

EXAMPLE 24 4-[3-[[[2-[(4-Cyclohexyl-1-piperazinyl)acetyl]-hydrazino]-carbonothioyl]amino]phenyl]1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylicAcid, Dimethyl Ester

[0110] This compound was isolated as a light yellow solid (73%): mpindistinct; ¹H NMR (DMSO-d₆) δ 8.99 (m, 1 H), 7.31 (m, 3 H), 6.92 (m, 1H), 4.95 (s, 1 H), 3.57 (m, 8 H), 3.09 (s, 1 H), 2.58 (m, 15 H), 1.82(m, 5 H), 1.21 (m, 4 H); ¹³C NMR (DMSO-d₆) 167.4, 149.1, 147.7, 146.1,145.9, 140.0, 128.6, 127.7, 115.9, 115.1, 101.3, 62.9, 59.5, 51.9, 51.0,48.1, 38.3, 27.8, 27.5, 25.3, 18.2. HRMS calculated for C₃₀H₄₃N₆O₅S(M+H): 599.3016. Found: 599.3030.

General Procedure for the Preparation of Oxadiazoles of Examples 25-27

[0111] A solution of the acylsemicarbazide (3.5 mmol) and 19 mL of POCl₃was heated on a steam bath until the reaction was judged complete by ticanalysis (45 minutes to 2 hours). The dark solution was cooled to roomtemperature, diluted with 100 mL of CH₂Cl₂ and the solution then pouredinto 300 mL of a stirred ice-water mixture. The mixture was allowed towarm to room temperature and then extracted with CH₂Cl₂/MeOH mixtures.The combined extracts were washed with H₂O, brine, and dried over MgSO₄.The volatiles were removed in vacuo and the residue purified by flashchromatography (SiO₂:EtOAc/MeOH). The following oxadiazole derivativeswere obtained:

EXAMPLE 254-[3-[[5-[4-(Methoxyphenyl)-1-piperidinyl]methyl]-1,3,4-oxadiazol-2-yl]amino]phenyl]-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate,Hydrochloride Salt

[0112] This compound was isolated as an orange-yellow solid (8%): mpindistinct. Analysis calculated for C₃₃H₃₇N₅O₆.2 HCl.1.60 H₂O: C, 56.56;H, 6.06; N, 9.99. Found: C, 56.56; H, 6.06; N, 9.77.

EXAMPLE 264-[3-[[5-[4-(3-Methoxyphenyl)-1-piperidinyl]ethyl]-1,3,4-oxadiazol-2-yl]amino]phenyl]-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate,Hydrochloride Salt

[0113] This compound was isolated as a yellow solid (30% yield): mp75-80° C. (sintered); ¹³C NMR (DMSO-d₆) δ 167.3, 160.0, 159.3, 156.3,148.4, 145.8, 145.8, 145.7, 138.4, 129.5, 128.6, 120.3, 118.6, 115.9,114.6, 112.6, 111.6, 101.1, 54.9, 52.6, 51.9, 51.8, 50.6, 38.2, 29.6,20.0, and 18.1. HRMS calculated for C₃₃H₄₀N₅O₆ (M+H): 602.2979. Found:602.2993.

EXAMPLE 274-[3-[[5-[3-[4-(3-Methoxyphenyl)-1-piperidinyl]propyl]-1,3,4-oxadiazol-2-yl]amino]phenyl]-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate,Hydrochloride Salt

[0114] This compound was isolated as a yellow solid (19% yield): mpindistinct; ¹H NMR (DMSO-d₆) δ 10.85 (br s, 1 H), 10.35 (s, 1 H), 9.03(s, 1 H), 7.37 (m, 2 H), 7.26 (t, 1 H, J=7.6 Hz), 7.16 (t, 1 H, J=1.8Hz), 6.79 (m, 4 H), 4.91 (s, 1 H), 3.75 (s, 3 H), 3.66 (s, 6 H), 3.19(m, 2 H), 3.05 (m, 2 H), 2.90 (t, 2 H, J=7.1 Hz), 2.80 (m, 1 H), 2.28(s, 6 H), 2.19 (m, 4 H), and 1.92 (m, 2 H); ¹³C NMR (DMSO-d₆) δ 167.4,159.9, 159.4, 158.7, 148.5, 146.0, 138.6, 129.7, 129.0, 120.3, 119.2,118.7, 116.0, 114.6, 112.7, 111.7, 101.2, 55.0, 52.0, 50.7, 38.7, 38.4,29.7, 22.1, 20.2, and 18.2. Analysis calculated for C₃₄H₄₁ N₅O₆.1.5HCl.0.33 H₂O: C, 60.22; H, 6.43; N, 10.33. Found: C, 60.22; H, 6.42; N,9.95.

General Procedure for the Preparation of Oxadiazoles of Examples 28-32

[0115] The starting acyl- or thioacylsemicarbazide (0.34 mmol) wasdissolved in 1,2-dichloroethane (10 mL). To this solution PPh₃ (0.41mmol), and CCl₄ (0.51 mmol) was added and the solution was stirred atreflux for 36 hours. The solvent was concentrated in vacuo and theresidue was purified by flash chromatography (SiO₂: MeOH/CH₂Cl₂). Thefollowing oxadiazole derivatives were obtained:

EXAMPLE 284-[3-[[5-[(4-Phenyl-1-piperidinyl)methyl]-1,3,4-oxadiazol-2-yl]amino]phenyl]-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate

[0116] After flash chromatography, this compound was isolated as anoff-white solid (54% yield): mp 118-123° C., sintered; ¹H NMR (DMSO-d₆)δ 10.4 (s, 1 H), 8.92 (s, 1 H), 7.27 (m, 9 H), 6.76 (d, 1 H, J=7.6 Hz),4.91 (s, 1 H), 3.71 (br s, 2 H), 3.57 (s, 6 H), 3.34 (s, 2 H), 2.95 (d,2 H, J=10.3 Hz), 2.23 (m, 8 H), 1.68 (m, 4 H); ¹³H NMR (DMSO-d₆) δ167.4, 160.2, 157.1, 148.4, 146.0, 145.9, 138.5, 128.7, 128.3, 126.7,126.0, 120.3, 115.9, 114.5, 101.1, 53.2, 51.5, 50.7, 41.3, 38.3, 32.9,18.2. HRMS calculated for C₃₁H₃₆N₅O₅ (M+H): 558.2717. Found: 558.2694.

EXAMPLE 294-[3-[[5-[(4-Phenyl-1-piperazinyl)methyl]-1,3,4-oxadiazol-2-yl]amino]phenyl]-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate

[0117] This compound was isolated as a pale yellow airy solid (78%yield), after chromatography: mp 115-125° C., sintered; ¹H NMR (DMSO-d₆)δ 10.4 (s, 1 H), 8.93 (s, 1 H), 7.38 (m, 2 H), 7.18 (m, 2 H), 6.92 (d, 2H, J=8.1 Hz), 6.77 (m, 2 H), 4.92 (s, 1 H), 3.75 (s, 2 H), 3.57 (s, 6H), 3.13 (m, 4 H), 2.63 (m, 4 H), 2.28 (s, 6 H); ¹³C NMR (DMSO-d₆) δ167.4, 160.3, 156.8, 150.9, 148.5, 145.9, 138.5, 128.9, 128.7, 120.3,118.9, 115.9, 115.5, 114.6, 101.1, 54.9, 52.2, 51.2, 50.7, 48.2, 38.3,18.2. Analysis calculated for C₃₀H₃₄N₆O₅.0.25 H₂O: C, 63.99; H, 6.18; N,14.92. Found: C, 63.80; H, 6.18; N, 14.65.

EXAMPLE 30 4-[3-[[5-[(4-Cyclohexyl-1-piperazinyl)methyl]-1,3,4-oxadiazol-2-yl]amino]phenyl]-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate

[0118] This compound was obtained as an orange solid (10% yield): mp158-162° C., sintered; ¹H NMR (DMSO-d₆) δ 10.4 (s, 1 H), 8.93 (s, 1 H),7.30 (m, 3 H), 6.78 (m, 1 H), 4.91 (s, 1 H), 3.83 (s, 1 H), 3.74 (s, 1H), 3.56 (s, 6 H), 3.16 (m, 8 H), 2.27 (s, 6 H), 1.44 (m, 11 H); ¹³C NMR(DMSO-d₆) δ 167.4, 156.0, 148.5, 145.8, 129.7, 128.7, 118.6, 112.5,101.1, 54.9, 50.7, 48.8, 47.9, 43.6, 38.3, 29.4, 26.3, 24.4, 18.2. HRMScalculated for C₃₀H₄₁N₆O₅ (M+H): 565.3139. Found: 565.3150.

EXAMPLE 314-[4-Fluoro-3-[[5-[[4-(3-methoxyphenyl-1-piperidinyl)methyl]-1,3,4-oxadiazol-2-yl]amino]phenyl]-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate

[0119] This compound was isolated as a pale yellow solid (34% yield): mp199-203° C.; ¹H NMR (DMSO-d₆) δ 10.1 (s, 1 H), 8.96 (s, 1 H), 7.98 (d, 1H, J=6.4 Hz), 7.19 (t, 1 H, J=7.7 Hz), 7.08 (m, 1 H), 6.77 (m, 4 H),4.92 (s, 1 H), 3.81 (m, 5 H), 3.58 (s, 6 H), 2.95 (d, 2 H, J=11.0 Hz),2.45 (m, 1 H), 2.22 (m, 8 H), 1.68 (m, 4 H); ¹³C NMR (DMSO-d₆) δ 167.3,160.4, 159.3, 157.7, 149.1, 147.7, 145.9, 144.0, 129.3, 125.9, 121.5,119.4, 118.9, 114.9, 112.5, 111.4, 101.2, 54.9, 53.2, 51.6, 50.7, 41.4,38.0, 32.8, 18.1. Analysis calculated for C₃₂H₃₆FN₅O₆.1.0 H₂O: C, 61.63;H, 6.14; N, 11.23. Found: C, 61.78; H, 5.94; N, 11.04.

EXAMPLE 324-[3-[[5-[(4-Piperdine-1-piperidinyl)methyl]-1,3,4-oxadiazol-2-yl]amino]phenyl]-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate

[0120] This compound was isolated as a yellow solid (28% yield): mpindistinct; ¹H NMR (DMSO=d₆) δ 10.5 (s, 1 H), 8.94 (s, 1 H), 7.41 (m, 2H), 7.18 (t, 1 H, J-7.9 Hz), 6.78 (d, 1 H, J=7.7 Hz), 4.91 (s, 1 H),3.55 (s, 6 H), 3.38 (m, 6 H), 2.84 (m, 4 H), 2.27 (s, 6 H), 2.14 (m, 2H), 1.77 (m, 6 H); ¹³C NMR (DMSO-d₆) δ 167.4, 160.7, 148.5, 145.9,138.2, 130.3, 128.7, 120.6, 116.2, 114.8, 101.1, 50.7, 49.2, 38.3, 24.3,22.7, 21.3, 18.2. LRMS m/z (ESI) 565.30 (M+H)⁺; HPLC retention time2.691.

EXAMPLE 33 Preparation of4-[3-[[5-[(4-Phenyl-1-piperidinyl)methyl]-1,3,4-thiadiazol-2-yl]amino]phenyl]-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate

[0121] A solution of the compound of Example 16 (0.25 g, 0.43 mmol) andLawesson's reagent (0.35 g, 0.87 mmol) in toluene (50 mL) was refluxedfor 2 hours. The mixture was cooled to room temperature, concentrated invacuo, and filtered over a pad of silica gel. Final purification wasachieved by preparatory HPLC. (10 mg, 4% yield) of compound was obtainedafter Prep HPLC: ¹³C NMR (CDCl₃) δ 168.1, 149.41, 146.9, 129.1, 127.6,126.7, 114.0, 102.2, 55.3, 53.4, 51.1, 38.7, 30.4, 19.1. HRMS calculatedfor C₃₁H₃₆N₅O₄S (M+H): 574.2488. Found: 574.2489.

EXAMPLE 34 Preparation of(±)1,4-Dihydro-4-[3-[[4-(ethoxy)1,2,5-thiadiaz-3-ole-1-oxide]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylicAcid, Hemihydrate

[0122] AlMe₃ (1.1 mL of a 2.0 M solution in hexanes; 2.2 mmol) was addedto a solution of requisite aniline (316 mg, 1.0 mmol) in CH₂Cl₂ (10 mL)at 0° C. The mixture was stirred for 30 minutes at 0° C., followed bythe addition of the thiadiazole (285 mg, 1.5 mmol). The reaction wasthen brought to reflux for 18 hours, cooled to 0° C., and quenched byslow addition of salt. NH₄Cl. The crude product was extracted withCH₂Cl₂, dried, and concentrated. The residue was chromatographed(CH₂Cl₂:MeOH 50:1) to afford the desired product (220 mg, 48%). mp191-197° C. ¹H NMR (DMSO-d₆): δ 10.30 (s, 1 H), 8.94 (s, 1 H), 7.84 (s,1 H), 7.64 (d, 1 H, J=8.0 Hz), 7.24 (t, 1 H, J=8.0 Hz), 6.94 (d, 1 H,J=8.0 Hz), 4.93 (s, 1 H), 4.55 (m, 2 H), 3.56 (s, 6 H), 2.27 (s, 6 H),1.45 (t, 3 H, J=7.1 Hz). ¹³C NMR (DMSO-d₆): δ 167.3, 164.0, 152.6,148.3, 145.9, 137.7, 128.4, 123.4, 119.5, 118.3, 101.0, 68.9, 50.7,38.4, 18.2, 13.8. Analysis calculated for C ₂₁H₂₄N₄O₆S.0.5 H₂O: C,53.72; H, 5.37; N, 11.93. Found: C, 53.94; H, 5.25; N, 12.17.

EXAMPLE 35 Preparation of(±)4-[3-[[3-[[4-(3-Methoxyphenyl)-1-piperidinyl]propyl]amino]1,2,5-thiadiaz-2-ole-1-oxide]amino]phenyl]-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylicAcid, Dimethyl Ester, Dihydrate

[0123] The thiadiazole of Example 34 (263 mg, 0.30 mmol) and thepiperdine of Compound XII (149 mg, 0.60 mmol) were combined in CH₃CN(3.0 mL) and stirred for 18 hours. The resulting solution wasconcentrated and chromatographed (CH₂Cl₂:MeOH, 10:1) to give thethiadiazole oxide (110 mg, 55%). mp 128-134° C. ¹H NMR (CDCl₃): δ 7.45(bs, 1 H), 7.11 (t, 1 H, J=7.8 Hz), 7.00 (d, 1 H, J=7.8 Hz), 6.68 (m, 6H), 6.36 (bs, 1 H), 4.97 (s, 1 H), 3.70 (s, 3 H), 3.54 (s, 6 H), 3.29(m, 1 H), 3.19 (m, 1 H), 2.98 (m, 2 H), 2.42 (m, 3 H), 2.26 (s, 3 H),2.19 (s, 3 H), 2.08 (m, 2 H), 1.75 (m, 6 H). ¹³C NMR (CDCl₃): δ 168.1,159.7, 159.2, 153.5, 148.2, 147.4, 145.5, 145.4, 137.7, 129.5, 128.7,124.4, 119.9, 119.2, 118.1, 112.9, 111.4, 103.1, 102.9, 55.8, 55.2,54.2, 54.1, 51.2, 51.1, 42.6, 42.2, 38.8, 32.9, 25.1, 19.7, 19.5.Analysis calculated for C₃₄H₄₂N₆O₆S.1.9 H₂O: C, 58.58; H, 6.62; N,12.05; Found: C, 58.97; H, 6.32; N, 11.65. HRMS calculated forC₃₄H₄₃N₆O₆S: 663.2965. Found: 663.2976.

[0124] While various embodiments are disclosed herein, these compoundsare intended to be exemplary of the invention. It will be appreciated byone skilled in the art that other compounds can be prepared withoutdeparting from the scope of the invention as defined in the appendedclaims.

1. A compound of Formula (I) and its pharmaceutically acceptable acidaddition salts or hydrates thereof

wherein B is

with X being O, S or

R¹ and R⁴ are independently selected from CO₂R⁶, cyano, and

where R⁶ is a lower alkyl; R² and R³ are independently selected fromhydrogen, cyano and lower alkyl; R⁵ is selected from hydrogen andhalogen; n is an integer selected from 1 to 5;

in which R⁷ and R⁸ are independently selected from lower alkyl and loweralkanol; R⁹ is selected from hydrogen, lower alkyl, —CO₂R⁶,—(CH₂)_(m)R¹⁰, hydroxy, cyano, and —(CH₂)_(m)NR¹¹R¹², wherein m is zeroor an integer from 1 to 3; R¹⁰ is C₃₋₇ cycloalkyl, naphthyl, and

with R¹³ selected from the group consisting of lower alkyl, loweralkenyl, C₃₋₇ cycloalkyl, lower alkoxy, hydrogen, halogen, hydroxy,dialkylamino, phenoxy, amino, —NHCOR⁶, —CO₂R⁶, NO₂, trifluoromethyl, andphenyl, and R¹¹ and R¹² are independently selected from the groupconsisting of hydrogen, alkyl, cycloalkyl, alkylene, phenyl, alkylamino,heterocyclic alkyl, methoxy, cyano, lower alkanol, naphthyl, furfuryl,tetrahydrofurfuryl, thiophene, azetidine, lower alkyl esters,acetamides, and carbamates and where —NR¹¹R¹² is a heterocyclic amine orimine.
 2. A compound of claim 1, wherein B is


3. A compound of claim 2 wherein Z is


4. A compound of claim 2 wherein Z is


5. A compound of claim 3 wherein R⁹ is


6. A compound of claim 1, wherein R¹ and R⁴ are —CO₂CH₃.
 7. The compoundof claim 1 wherein n is 1, 2 or
 3. 8. The compound of claim 1 wherein Zis

and R⁹ is 3-methoxyphenyl, phenyl or cyclohexyl.
 9. The compound ofclaim 1 wherein B is

and Z is


10. The compound of claim 9 wherein R⁹ is 3-methyoxyphenyl or phenyl.11. The compound of claim 1 wherein B is


12. The compound of claim 11 wherein Z is 3-methoxyphenylpiperidinyl.13. The compound of claim 1 selected from the group consisting of4-[3-[[[2-[4-(3-Methoxyphenyl)-1-piperidinyl]acetyl]hydrazino]carbonyl]amino]phenyl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylicacid, dimethyl ester;4-[3-[[[2-[3-[4-(3-Methoxyphenyl)-1-piperidinyl]-1-oxopropyl]hydrazino]carbonyl]amino]phenyl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylicacid, dimethyl ester;4-[3-[[[2-[4-[4-(3-Methoxyphenyl)-1-piperidinyl]-1-oxobutyl]hydrazino]carbonyl]amino]phenyl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylicacid, dimethyl ester;4-[3-[[[2-[(4-Phenyl-1-piperidinyl)acetyl]-hydrazino]-carbonyl]amino]phenyl]1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylicacid, dimethyl ester;4-[3-[[[2-[(4-Phenyl-1-piperidinyl)acetyl]-hydrazino]-carbonothioyl]amino]phenyl]1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylicacid, dimethyl ester;4-[3-[[[2-[[4-(3-Methoxyphenyl)-1-piperidinyl)acetyl]-hydrazino]-carbonothioyl]amino]phenyl]1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylicacid, dimethyl ester;4-[3-[[[2-[(4-Phenyl)-1-piperazinyl]acetyl]-hydrazino]-carbonothioyl]amino]phenyl]1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylicacid, dimethyl ester;4-[4-Fluoro-3-[[[2-[[4-(3-methoxyphenyl)-1-piperidinyl]acetyl]-hydrazino]-carbonothioyl]amino]phenyl]1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylicacid, dimethyl ester;4-[3-[[[2-[[4-(1-Piperidinyl)-1-piperidinyl]acetyl]-hydrazino]-carbonothioyl]amino]phenyl]1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylicacid, dimethyl ester; and 4-[3-[[[2-[(4-Cyclohexyl-1-piperazinyl)acetyl]-hydrazino]-carbonothioyl]amino]phenyl]1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylicacid, dimethyl ester.
 14. The compound of claim 1 selected from thegroup consisting of4-[3-[[5-[4-(Methoxyphenyl)-1-piperidinyl]methyl]-1,3,4-oxadiazol-2-yl]amino]phenyl]-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate,hydrochloride salt;4-[3-[[5-[4-(3-Methoxyphenyl)-1-piperidinyl]ethyl]-1,3,4-oxadiazol-2-yl]amino]phenyl]-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate,hydrochloride salt; and4-[3-[[5-[3-[4-(3-Methoxyphenyl)-1-piperidinyl]propyl]-1,3,4-oxadiazol-2-yl]amino]phenyl]-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate,hydrochloride salt.
 15. The compound of claim 1 selected from the groupconsisting of4-[3-[[5-[(4-Phenyl-1-piperidinyl)methyl]-1,3,4-oxadiazol-2-yl]amino]phenyl]-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate;4-[3-[[5-[(4-Phenyl-1-piperazinyl)methyl]-1,3,4-oxadiazol-2-yl]amino]phenyl]-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate;4-[3-[[5-[(4-Cyclohexyl-1-piperazinyl)methyl]-1,3,4-oxadiazol-2-yl]amino]phenyl]-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate;4-[-fluoro-3-[[5-[[4-(3-Methoxyphenyl-1-piperidinyl)methyl]-1,3,4-oxadiazol-2-yl]amino]phenyl]-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate;and4-[3-[[5-[(4-Piperdine-1-piperidinyl)methyl]-1,3,4-oxadiazol-2-yl]amino]phenyl]-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate.16. The compound of claim 1 selected from the group consisting of4-[3-[[5-[(4-Phenyl-1-piperidinyl)methyl]-1,3,4-thiadiazol-2-yl]amino]phenyl]-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate;(±) 1,4-Dihydro-4-[3-[[4-(ethoxy)1,2,5-thiadiaz-3-ole-1-oxide]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylicacid, hemihydrate; and(±)4-[3-[[3-[[4-(3-Methoxyphenyl)-1-piperidinyl]propyl]amino]1,2,5-thiadiaz-2-ole-1-oxide]amino]phenyl]-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylicacid, dimethyl ester, dihydrate.
 17. A method of promoting weight lossand treating eating disorders in a mammal comprising administering to amammalian host an anorexiant effective dose of a compound claimed inclaim
 1. 18. A method of treating clinical disorders amenable toalleviation by eliciting an NPY Y₁ response, comprising administering toa patient suffering from such a disorder an effective amount of acompound claimed in claim
 1. 19. A pharmaceutical composition for use inpromoting weight loss and treating eating disorders, the compositioncomprising an anorexiant effective amount of a compound claimed in claim1 in combination with a pharmaceutically acceptable carrier.